The long-range objective of the proposed project is to conduct genetic research designed to generate useful information about individual differences in susceptibility to smoking and nicotine dependence. The specific aims are (1) to crease a phenotype and genotype registry to support genetic research on smoking; (2) to identify key phenotypic characteristics for smoking by taking into account the contribution of both susceptibility to nicotine dependence and other risk factors for smoking in smoking probands and first order relatives; and (3) to re- examine recent claims of genetic association between polymorphic variations in certain candidate genes and smoking behavior. The proposed study will involve 150 probands (75 males and 75 females) who are current smokers, same-sex full siblings who are nicotine-exposed never smokers and two living biological parents willing to answer questions about smoking and risk factors and to provide blood samples for DNA analysis (total N=600) Phenotypic data gathered will include a battery of instruments assessing co-factors for smoking (e.g., depression, ADHD, anxiety); personality measures (e.g., novelty-seeking); and variables believed to be associated with likelihood of smoking initiation (e.g., experience upon early experimentation with smoking); in addition, measures of nicotine dependence will be collected in all smokers and ex- smokers. Genotypic information will consist of candidate-gene markers for smoking risk factors, DRD2, DRD4, SLC6A3 [DAT1], and SLC6A4 [5-HTT] (polymorphisms associated with increased risk of depression, attention deficit, novelty seeking, anxiety), and for nicotine dependence, nAChRbeta2 (associated with nicotine reinforcement). Cigarette smoking is associated with over 450,000 premature deaths in the United States each year--25% of all deaths-- a figure that includes more than 100,000 deaths per year from bronchogenic carcinoma. The pathophysiological consequences of the habit account for nearly 60% of all direct health costs, with expenditures estimated to exceed one billion dollars a day. Increased knowledge about the genetics of smoking will be needed in substantial improvements in the management of cigarette smoking and consequent reduction in cancer morbidity and mortality are to be achieved.